RESUMEN
Three consecutive skeletal muscle biopsies during a several months time-frame, showing different degrees of neutral lipid storage. This is highlighted by Oil-red-O stains (D, E, F) and electron microscopy (G, H, I). Note the impact on mitochondrial morphology with so called 'parking lots (K, L). Zooming 'in and out' into the ultrastructure, using the nanotomy platform provides interesting detailled information (http://nanotomy.org). â.
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Errores Innatos del Metabolismo Lipídico , Enfermedades Musculares , Distrofias Musculares , Humanos , Inmunoglobulinas , Errores Innatos del Metabolismo Lipídico/patología , Músculo Esquelético/patología , Enfermedades Musculares/patología , Enfermedades Musculares/terapia , PlasmaféresisRESUMEN
BACKGROUND: Mutations in SLC25A4 (syn. ANT1, Adenine nucleotide translocase, type 1) are known to cause either autosomal dominant progressive external ophthalmoplegia (adPEO) or recessive mitochondrial myopathy, hypertrophic cardiomyopathy, and lactic acidosis. METHODS AND RESULTS: Whole exome sequencing in a young man with myopathy, subsarcolemmal mitochondrial aggregations, cardiomyopathy, lactic acidosis, and L-2-hydroxyglutaric aciduria (L-2-HGA) revealed a new homozygous mutation in SLC25A4 [c.653A>C, NM_001151], leading to the replacement of a highly conserved glutamine by proline [p.(Q218P); NP_001142] that most likely affects the folding of the ANT1 protein. No pathogenic mutation was found in L2HGDH, which is associated with "classic" L-2-HGA. Furthermore, L-2-HGDH enzymatic activity in the patient fibroblasts was normal. Long-range PCR and Southern blot confirmed absence of mtDNA-deletions in blood and muscle. CONCLUSION: The disturbed ADP/ATP transport across the inner mitochondrial membrane may lead to an accumulation of different TCA-cycle intermediates such as 2-ketoglutarate (2-KG) in our patient. As L-2-HG is generated from 2-KG we hypothesize that the L-2-HG increase is a secondary effect of 2-KG accumulation. Hence, our report expands the spectrum of laboratory findings in ANT1-related diseases and hints towards a connection with organic acidurias.
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We describe two sisters from a consanguineous Arab family with global developmental delay, dystrophy, axial hypotonia, epileptic encephalopathy dominated by intractable complex partial seizures that were resistant to various anti-epileptic treatments. Dysmorphic features comprised low set ears, hypertelorism, upslanting palpebral fissures, a broad nasal bridge, and blue sclera with elongated eyelashes. Brain MRI in both children showed a corpus callosum hypoplasia that was evident already in utero and evolving cortical atrophy. Autozygosity mapping in combination with Whole Exome Sequencing revealed a homozygous missense mutation in the PIGO gene [c.765G > A, NM_032634.3] that affected a highly conserved methionine in the alkaline phosphatase-like core domain of the protein [p.(Met255Ile), NP_116023.2]. PIGO encodes the GPI-ethanolamine phosphate transferase 3, which is crucial for the final synthetic step of the glycosylphosphatidylinositol-anchor that attaches many enzymes to their cell surfaces, such as the alkaline phosphatase and granulocyte surface markers. Interestingly, measurement of serum alkaline phosphatase activities in both children was normal or only slightly elevated. Quantification of granulocyte surface antigens CD16/24/59 yielded reduced levels only for CD59. Phenotype analysis of our and other published patients with PIGO mutations reveals a more severe affectation and predominantly neurological presentation in individuals carrying a mutation in the alkaline phosphatase-like core domain thereby hinting towards a genotype-phenotype relation for PIGO gene mutations.
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Agenesia del Cuerpo Calloso/genética , Fosfatasa Alcalina/sangre , Encéfalo/diagnóstico por imagen , Proteínas de la Membrana/genética , Mutación , Espasmos Infantiles/genética , Agenesia del Cuerpo Calloso/sangre , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Preescolar , Femenino , Homocigoto , Humanos , Lactante , Espasmos Infantiles/sangre , Espasmos Infantiles/diagnóstico por imagen , UltrasonografíaRESUMEN
BACKGROUND: Congenital muscular dystrophies (CMD) with hypoglycosylation of α-dystroglycan are clinically and genetically heterogeneous disorders that are often associated with brain malformations and eye defects. Presently, 16 proteins are known whose dysfunction impedes glycosylation of α-dystroglycan and leads to secondary dystroglycanopathy. OBJECTIVE: To identify the cause of CMD with secondary merosin deficiency, hypomyelination and intellectual disability in two siblings from a consanguineous family. METHODS: Autozygosity mapping followed by whole exome sequencing and immunochemistry were used to discover and verify a new genetic defect in two siblings with CMD. RESULTS: We identified a homozygous missense mutation (c.325C>T, p.Q109*) in protein O-mannosyl kinase (POMK) that encodes a glycosylation-specific kinase (SGK196) required for function of the dystroglycan complex. The protein was absent from skeletal muscle and skin fibroblasts of the patients. In patient muscle, ß-dystroglycan was normally expressed at the sarcolemma, while α-dystroglycan failed to do so. Further, we detected co-localisation of POMK with desmin at the costameres in healthy muscle, and a substantial loss of desmin from the patient muscle. CONCLUSIONS: Homozygous truncating mutations in POMK lead to CMD with secondary merosin deficiency, hypomyelination and intellectual disability. Loss of desmin suggests that failure of proper α-dystroglycan glycosylation impedes the binding to extracellular matrix proteins and also affects the cytoskeleton.
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Pérdida Auditiva/complicaciones , Discapacidad Intelectual/complicaciones , Laminina/deficiencia , Distrofias Musculares/congénito , Mutación/genética , Vaina de Mielina/patología , Proteínas Quinasas/genética , Adolescente , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Familia , Femenino , Pérdida Auditiva/enzimología , Pérdida Auditiva/genética , Humanos , Inmunohistoquímica , Lactante , Recién Nacido , Discapacidad Intelectual/enzimología , Discapacidad Intelectual/genética , Masculino , Datos de Secuencia Molecular , Músculo Esquelético/patología , Distrofias Musculares/complicaciones , Distrofias Musculares/enzimología , Distrofias Musculares/genética , Linaje , Adulto JovenRESUMEN
In this matched cohort study, clinical data from 43 paediatric cancer patients with bloodstream infection (BSI) were compared with 43 thoroughly matched control patients without BSI. BSI led to a median additional length of inpatient treatment of 12 days (IQR 8.5-16 days; P<0.001), accounting for median additional expenses of euro4400 (IQR, euro3145-5920) per case [6.970 US Dollar (IQR 4.938-9.294)]. Thus, BSI substantially increased financial resources required for inpatient treatment. These data compiled from a paediatric cancer unit may be utilized to estimate the cost-benefit ratio of targeted preventive measures.
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Bacteriemia/economía , Infecciones Relacionadas con Catéteres/economía , Infección Hospitalaria/economía , Hospitales Pediátricos/economía , Tiempo de Internación/economía , Neoplasias/complicaciones , Adolescente , Bacteriemia/complicaciones , Bacteriemia/microbiología , Instituciones Oncológicas/economía , Estudios de Casos y Controles , Infecciones Relacionadas con Catéteres/complicaciones , Infecciones Relacionadas con Catéteres/microbiología , Catéteres de Permanencia/microbiología , Niño , Preescolar , Estudios de Cohortes , Costos y Análisis de Costo , Infección Hospitalaria/complicaciones , Infección Hospitalaria/microbiología , Femenino , Alemania , Hospitalización/economía , Humanos , Lactante , MasculinoRESUMEN
One thousand five hundred sixty-eight RSV infections were documented prospectively in 1,541 pediatric patients. Of these, 20 (1.3%) had acquired the RSV infection while treated by mechanical ventilation for reasons other than the actual RSV infection (group ventilated mechanically). The clinical characteristics of children who were infected with respiratory syncytial virus (RSV) infection while ventilated mechanically for other reasons are described and compared with a matched control group. Sixty percent of the group ventilated mechanically had at least one additional risk factor for a severe course of infection (prematurity 50%, chronic lung disease 20%, congenital heart disease 35%, immunodeficiency 20%). The median age at diagnosis in the group ventilated mechanically was 4.2 months. The matched pairs analysis (group ventilated mechanically vs. control group) revealed a higher proportion of patients with hypoxemia and apnoea in the group ventilated mechanically; more patients in the control group showed symptoms of airway obstruction (wheezing). At least one chest radiography was performed in 95% of the patients (n = 19) in the group ventilated mechanically versus 45% (n = 9) in the control group (P = 0.001). The frequency of pneumonia was 40% in the group ventilated mechanically and 20% in the control group. Despite existing consensus recommendations, only two patients (10%) of the group ventilated mechanically had received palivizumab previously. Significantly more patients in the group ventilated mechanically received antibiotic treatment (85% vs. 45%, P = 0.008), and attributable mortality was higher in the group ventilated mechanically (15% [n = 3] vs. 0% in the control group, P = 0.231). Children treated by long term mechanical ventilation may acquire RSV infection by transmission by droplets or caregivers and face an increased risk of a severe course of RSV infection. The low rate of immunoprophylaxis in this particular risk group should be improved.